1. Field of the Invention
This invention is in the field of topical formulations for wound healing. In particular, the present invention relates to a novel composition for accelerating wound and ulcer healing. The topical formulation described herein is especially useful in the treatment of ulcers of diabetic patients.
2. Background Information
Indolent wounds, where healing either completely fails to take place or starts and subsequently fails to progress, present major problems. This particularly applies in elderly patients and in healing of wounds adjacent bony prominences.
A patient population for which wound healing is particularly difficult involves those with Type I or Type II diabetes. Progression of the diabetic state usually results in diminished circulation and a concomitant lessening of the blood supply to the extremities of the body. Thus, wounds among the diabetic population, particularly those wounds that are sustained on the feet or legs, suffer from a lack of the circulating nutrients necessary for the wound healing to occur.
The wound healing process has been the subject of much study. In order to discuss wounds a classification is necessary. While wounds are classified using different systems, the traditional system is the Wagner classification system. Wagner classifies wounds by their depth and also whether or not the site is infected. Medical procedures include progressive monitoring of wound condition using the original classification and measurement.
The role of antibiotics in wound healing is of interest. When infection is present in the wound, antibiotics are necessary to overcome the infection even though at therapeutically effective levels antibiotics irritate the wound site. While the mechanism of wound healing is not fully understood, it is known that certain polypeptides and antibiotics, especially polypeptide antibiotics, inhibit proteinases, particularly healing-disruptive matrix metalloproteinases (MMP's). As will become apparent from the description that follows, the use of even subantimicrobial levels of antibiotics have been found to irritate wounds and interfere with the healing process.
According to Wound Healing; an Overview of Acute, Fibrotic and Delayed Healing by Diegelmann et al. (Frontiers in Bioscience 9, 283-239, Jan. 1, 2004), acute wounds normally heal in a very orderly and efficient manner characterized by four distinct, but overlapping phases: hemostasis, inflammation, proliferation and remodeling. Specific biological markers characterize healing of acute wounds. Likewise, unique biologic markers also characterize pathologic responses resulting in fibrosis and chronic non-healing ulcers.
Diegelmann et al. further indicate that the normal healing response begins the moment the tissue is injured. As the blood components spill into the site of injury, the platelets come into contact with exposed collagen and other elements of the extracellular matrix. This contact triggers the platelets to release clotting factors as well as essential growth factors and cytokines such as platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-B). Following hemostasis, the neutrophils then enter the wound site and begin the critical task of phagocytosis to remove foreign materials, bacteria and damaged tissue. As part of this inflammatory phase, the macrophages appear and continue the process of phagocytosis as well as releasing more PDGF and TGFB. Once the wound site is cleaned, fibroblasts migrate in to begin the proliferative phase and deposit new extracellular matrix. The new collagen matrix then becomes cross-linked and organized during the final remodeling phase. In order for this efficient and highly controlled repair process to take place, there are numerous cell-signaling events that are required.
In indolent wounds such as non-healing ulcers, this efficient and orderly process that Diegelmann et al. describe is lost and the ulcers are locked into a state of chronic inflammation, characterized by abundant neutrophil infiltration with associated reactive oxygen species and destructive enzymes. Healing proceeds only after the inflammation is controlled. Thus it is believed that wounds and ulcers that do not heal contain an excessive amount of neutrophils. The neutrophils, in turn, produce metalloproteinases (MMP's). MMP's break down the extracellular matrix (ECM), which connects cells together to form tissue. If MMP's dominate, the tissue necessary to repair the wound will not form. The body has some natural MMP inhibitors tissue inhibitors of metalloproteinases (TIMP's). Supplementation with added MMP inhibitors ensures sufficient inhibition for wound healing. For the typical formulation taught herein, subantimicrobial amounts of polypeptide antibiotics serve as proteinase inhibitors.
In the literature, subantimicrobial amounts of non-polypeptide antibiotics are also described a MMP inhibitors. An example of this is noted in November 2006 Periodontal Disease review by Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital, wherein doxycycline is an MMP inhibitor. There have also been polypeptide chains that have inhibited MMP's. U.S. Pat. No. 7,148,194 describes that these polypeptide chains called proenzyme leader sequences impact healing by re-forming MMP's to their undifferentiated, proenzyme state and thereby inhibiting the destructive enzymatic activity.
The healing mechanism and the effect of polypeptide antibiotics on wound healing are not fully understood. As taught by the inventor hereof, near trace amounts of polypeptide antibiotics work to heal wounds, while higher amounts of polypeptide antibiotics (still in the subantimicrobial range) irritate the wound and prevent healing.
Vitamin D and its analogs have been mentioned in the prior art as suitable therapeutics for the treatment of indolent wounds, especially for the healing of decubitus or diabetic ulcers of the feet. Of note in connection to this is U.S. Pat. No. 5,254,538 to Holick et al. entitled Method of Treating Periodontal Disease, which is hereby incorporated by reference in its entirety. Also noted are the references cited therein. However, there still exists a need for a specific therapy for the healing of wounds which are resistant to standard therapeutic agents. Accordingly, the present invention is directed to these ends.